Ovarian Cancer Protection from Oral Contraceptives Is Greatest with the Lowest Doses of Hormones

Oral contraceptive use has a well-established association with a reduced risk of ovarian cancer; new evidence from a population-based case-control study suggests that pills with the lowest hormonal content offer the greatest protection.1 The odds of ovarian cancer were reduced by up to 80% among pill users, depending on the oral contraceptive formulation. Furthermore, the lower the dose of one particular progestin, the lower the risk of ovarian cancer. If all women had used some type of birth control pill, an estimated four in 10 malignancies might have been avoided; if all had used low-dose pills, that proportion would have been almost three-quarters.

Using data from two rapid-response systems, researchers identified residents of Hawaii and Los Angeles aged 18 and older in whom ovarian cancer was diagnosed between 1993 and 2005; they obtained information about tumor stage, grade and histology from pathology and surgical reports. A control group of women aged 18 and older with no history of ovarian cancer was randomly selected from among respondents to an annual household survey in Hawaii and by random digit dialing in Los Angeles. Participants completed interviews covering demographic, socioeconomic, health-related and contraceptive information; interviewers used monthly calendars and pictures of various oral contraceptives to help women provide detailed information about their reproductive history and pill use.

The analyses included 745 women with cancer and 943 controls. In both groups, women were, on average, about 56 years old; the vast majority were Asian or white. Women with cancer had had significantly less education and fewer pregnancies than controls, and were more likely to have a family history of ovarian cancer. They were significantly less likely to have been sterilized, to be premenopausal and to be using combined hormone therapy.

A total of 868 women (317 women with cancer and 551 controls) had ever used combination oral contraceptives and provided the information necessary for the researchers to determine the potency (low vs. high) of each hormonal component. Forty percent of ever-users had taken pills with a low concentration of estrogen (0.035 mg or less of ethinyl estradiol), and 10% had taken pills with a low concentration of progestin (less than 0.3 mg of norgestrel). These women had used oral contraceptives more recently than those who had used higher potency formulations, but they had used the pill for longer durations.

In analyses controlling for a wide range of potentially confounding variables, ever-use of oral contraceptives was associated with significantly reduced odds of ovarian cancer (odds ratios, 0.5 overall; 0.6 in analyses adjusted for duration of use). Associations were significant for women who had taken pills with high doses of both hormones (0.6), low doses of both (0.2), or a low dose of estrogen combined with a high dose of progestin (0.5); differences among pill formulations were not statistically significant. The researchers estimate that use of any combined oral contraceptive might have averted 42% of ovarian cancers and that use of pills with low doses of estrogen and progestin might have prevented 73% of malignancies.

A similar pattern was observed in analyses restricted to women with invasive ovarian cancer. Compared with women who had never used the pill, ever-users had 46% lower odds of invasive cancer; significant reductions were found regardless of pill formulation. Both the overall results and those for invasive cancer were essentially the same for women younger than 55 (the only ones exposed solely to low-dose pills) as for the entire cohort.

A final set of analyses examined the ovarian cancer risk in relation to ever-use of monophasic pills containing the progestin norethindrone. These calculations showed a significantly reduced risk of disease associated with use of any such oral contraceptive (odds ratio, 0.6). The risk was dramatically lower among women who had used pills with 0.4–0.5 mg of norethindrone (0.1) than among those whose pills had contained 10 mg of the progestin; it decreased significantly as the dose of norethindrone declined.

The researchers acknowledge a number of shortcomings of their study, including the possibility of nonresponse bias and reliance on participants’ recall. However, they also point to some distinctive strengths—particularly, that the cohort included enough women providing detailed information about pill use to permit important subgroup analyses. Noting that declines in ovarian cancer rates in the United States are partly attributable to oral contraceptive use, the researchers conclude that studies involving larger numbers of women are needed so that the association between low-dose pill use and ovarian risk can be better understood.
—D. Hollander